Amides of acetic and propionic acids

ABSTRACT

The invention relates to novel amides of acetic and propionic acids, methods for production and use thereof for the production of medicaments for the treatment and/or prophylaxis of diseases and for improving perception, concentration, learning ability and memory.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/968,536, filed Aug. 16, 2013, which application is a continuation ofU.S. patent application Ser. No. 12/494,009, filed Jun. 29, 2009, nowU.S. Pat. No. 8,518,967 on Aug. 27, 2013, which application is acontinuation of U.S. patent application Ser. No. 10/508,106 filed May 6,2005, now U.S. Pat. No. 7,553,851, which is the U.S. National Stageapplication under 35 U.S.C. §371 of International Patent ApplicationSerial No. PCT/EP03/02152, filed Mar. 3, 2003, which claims the benefitof German Patent Application No. 102 11 416.1, filed Mar. 15, 2002, thedisclosures of each of which are expressly incorporated by reference intheir entireties.

The invention relates to novel amides of acetic and propionic acids, toa process for the preparation thereof and to the use thereof forproducing medicaments for the treatment and/or prophylaxis of diseasesand for improving perception, concentration, learning and/or memory.

Nicotinic acetylcholine receptors (nAChR) form a large family of ionchannels which are activated by the messenger acetylcholine which isproduced in the body (Galzi and Changeux, Neuropharmacol. 1995, 34,563-582). A functional nAChR consists of five subunits which may bedifferent (certain combinations of α1-9 and β1-4,γ,δ,ε subunits) oridentical (α7-9). This leads to the formation of diversity of subtypeswhich differ in the distribution in the muscles, the nervous system andother organs (McGehee and Role, Annu. Rev. Physiol. 1995, 57, 521-546).Activation of nAChR leads to influx of cations into the cell and tostimulation of nerve cells or muscle cells. Selective activation ofindividual nAChR subtypes restricts this stimulation to the cell typeswhich have the corresponding subtype and is thus able to avoid unwantedside effects such as, for example, stimulation of nAChR in the muscles.Clinical experiments with nicotine and experiments in various animalmodels indicate that central nicotinic acetylcholine receptors areinvolved in learning and memory processes (e.g. Rezvani and Levin, Biol.Psychiatry 2001, 49, 258-267). Nicotinic acetylcholine receptors of thealpha7 subtype (α7 nAChR) have a particularly high concentration inregions of the brain which are important for learning and memory, suchas the hippocampus and the cerebral cortex (Séguéla et al., J. Neurosci.1993, 13, 596-604). The α7 nAChR has a particularly high permeabilityfor calcium ions, increases glutamatergic neurotransmission, influencesthe growth of axons and, in this way, modulates neuronal plasticity(Broide and Leslie, Mol. Neurobiol. 1999, 20, 1-16).

Certain quinuclidinecarboxanilides are described as antiarrhythmics andlocal anesthetics (cf., for example, FR. 1.566.045, GB 1 578 421 andOppenheimer et al, Life Sci. 1991, 48, 977-985).

WO 01/60821 discloses biarylcarboxamides with affinity for the α7 nAChRfor the treatment of learning and perception impairments.

The present invention relates to compounds of the general formula (I)

in which

-   R¹ is a 1-azabicyclo[m.n.p]alkyl radical having 7 to 11 ring atoms,    -   in which m and n are independently of one another 2 or 3,    -   in which p is 1, 2 or 3,    -   and where the bicycloalkyl radical is optionally substituted by        (C₁-C₆)-alkyl,-   A is methylene or ethylene,-   R² is 8- to 10-membered heteroaryl, naphthyl or azulenyl, where the    rings are optionally substituted by radicals selected from the group    of halogen, formyl, —CO—NR⁴R⁵, —CO—OR⁶, —NR⁷R⁸, —NR⁹—CO—R¹⁰, cyano,    trifluoromethyl, trifluoromethoxy, nitro, optionally hydroxyl-,    amino-, —NH—CO—R¹¹— or cyano-substituted (C₁-C₆)-alkyl,    (C₁-C₆)-alkoxy, (C₁-C₆)-alkylthio,    -   in which R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are independently        of one another hydrogen, (C₁-C₆)-alkyl, phenyl or benzyl,        and-   R³ is hydrogen or (C₁-C₆)-alkyl.

The compounds of the invention may exist in stereoisomeric forms whicheither are related as image and mirror image (enantiomers) or which arenot related as image and mirror image (diastereomers). The inventionrelates both to the enantiomers or diastereomers or respective mixturesthereof. These mixtures are enantiomers and diastereomers which can beseparated in a known manner into the stereoisomerically pureconstituents.

The compounds of the invention may also be in the form of their salts,solvates or solvates of the salts.

Salts which are preferred for the purposes of the invention arephysiologically acceptable salts of the compounds of the invention.

Physiologically acceptable salts of the compounds of the invention maybe acid addition salts of the compounds with mineral acids, carboxylicacids or sulfonic acids. Particularly preferred examples are salts withhydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid,benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionicacid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acidor benzoic acid.

However, salts which may be mentioned are also salts with conventionalbases, such as, for example, alkali metal salts (e.g. sodium orpotassium salts), alkaline earth metal salts (e.g. calcium or magnesiumsalts) or ammonium salts derived from ammonia or organic amines such as,for example, diethylamine, triethylamine, ethyldiisopropylamine,procaine, dibenzylamine, N-methylmorpholine, dihydro-abietylamine,1-ephenamine or N-methylpiperidine.

Solvates is the term used for the purposes of the invention for thoseforms of the compounds which form a complex with solvent molecules bycoordination in the solid or liquid state. Hydrates are a special formof solvates in which the coordination takes place with water.

For the purposes of the present invention, the substituents generallyhave the following meaning:

(C₁-C₆)- and (C₁-C₄)-alkoxy stands for a straight-chain or branchedalkoxy radical respectively having 1 to 6 and 1 to 4 carbon atoms.Preference is given to a straight-chain or branched alkoxy radicalhaving 1 to 4, particularly preferably having 1 to 3, carbon atoms. Thefollowing may be mentioned by way of example and preferably: methoxy,ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

(C₁-C₆)- and (C₁-C₄)-alkyl stand for a straight-chain or branched alkylradical respectively having 1 to 6 and 1 to 4 carbon atoms. Preferenceis given to a straight-chain or branched alkyl radical having 1 to 4,particularly preferably having 1 to 3, carbon atoms. The following maybe mentioned by way of example and preferably: methyl, ethyl, n-propyl,isopropyl, tert-butyl, n-pentyl and n-hexyl.

(C₁-C₆)-Alkylthio stands for a straight-chain or branched alkylthioradical having 1 to 6 carbon atoms. Preference is given to astraight-chain or branched alkylthio radical having 1 to 4, particularlypreferably having 1 to 3, carbon atoms. The following may be mentionedby way of example and preferably: methylthio, ethylthio, n-propylthio,isopropylthio, tert-butylthio, n-pentylthio and, n-hexylthio.

The 1-azabicyclo[m.n.p]alkyl radical having 7 to 11 ring atoms ispreferably and by way of example: 1-azabicyclo[3.2.1]octyl (isotropane),1-azabicyclo[3.3.1]nonyl (isogranatane), 1-azabicyclo[2.2.2]octyl(quinuclidine).

Halogen Stands for fluorine, chlorine, bromine and iodine. Fluorine,chlorine and bromine are preferred. Fluorine and chlorine areparticularly preferred.

8- to 10-membered heteroaryl stands for an aromatic bicyclic radicalhaving 8 to 10, preferably 9 to 10, ring atoms and up to 5, preferablyup to 4, heteroatoms from the series S, O and/or N. The heteroarylradical may be bonded via a carbon atom or heteroatom. The following maybe mentioned by way of example and preferably: indolyl, indazolyl,benzofuranyl, benzothiophenyl, quinolizinyl, isoquinolinyl.

If radicals in the compounds of the invention are optionallysubstituted, the radicals may, unless specified otherwise, besubstituted one or more times, identically or differently. Substitutionwith up to three identical or different substituents is preferred.

Preferred compounds of the general formula (I) are those in which

-   R¹ is 1-azabicyclo[2.2.2]octyl.

Particularly preferred compounds of the general formula (I) are those inwhich

-   R¹ is 1-azabicyclo[2.2.2]oct-3-yl.

Likewise preferred compounds of the general formula (I) are those inwhich

-   A is methylene.

Likewise preferred compounds of the general formula (I) are those inwhich

-   R² is 9- to 10-membered heteroaryl or naphthyl, where the rings are    optionally substituted by 1 to 3 radicals selected from the group of    hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro,    (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy and (C₁-C₄)-alkylthio.

Particularly preferred compounds of the general formula (I) are those inwhich

-   R² is indolyl, benzoimidazolyl, benzotriazolyl, benzothiophenyl,    benzofuranyl, quinolinyl, isoquinolyl, benzopyrazinyl,    benzopyrimidinyl, benzopyridizanyl or naphthyl, where the rings are    optionally, substituted by 1 to 3 radicals selected from the group    of hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy,    nitro, (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, (C₁-C₄)-alkylthio.

Very particularly preferred compounds of the general formula (I) arethose in which

-   R² is benzotriazolyl, benzothiophenyl, quinolinyl, benzopyrazinyl or    naphthyl, where the rings are optionally substituted by 1 to 3    radicals selected from the group of hydrogen, halogen, cyano,    trifluoromethyl, trifluoromethoxy, nitro, (C₁-C₄)-alkyl,    (C₁-C₄)-alkoxy, (C₁-C₄)-alkylthio

The most preferred compounds of the general formula (I) are those inwhich

-   R² is benzothiophen-2-yl, which is optionally substituted by 1 to 3    radicals selected from the group of hydrogen, halogen, cyano,    trifluoromethyl and C₁-C₄)-alkyl.

Likewise preferred compounds of the general formula (I) are those inwhich

-   R³ is hydrogen or methyl.

Particularly preferred compounds of the general formula (I) are those inwhich

-   R³ is hydrogen.

Combinations of two or more of the abovementioned preferred ranges arevery particularly preferred.

Likewise very particularly preferred compounds of the general formula(I) are those in which

-   R¹ is 1-azabicyclo[2.2.2]oct-3-yl,-   A is methylene,-   R² is benzotriazolyl, benzothiophenyl, quinolinyl, benzopyrazinyl or    naphthyl, where the rings are optionally substituted by 1 to 3    radicals selected from the group of hydrogen, halogen, cyano,    trifluoromethyl, trifluoromethoxy, nitro, (C₁-C₄)-alkyl,    (C₁-C₄)-alkoxy, (C₁-C₄)-alkylthio,    and-   R³ is hydrogen.

Likewise very particularly preferred are compounds of the generalformula (I), in which

-   R¹ is 1-azabicyclo[2.2.2]oct-3-yl,-   A is methylene,-   R² is benzothiophenyl, quinolinyl or naphthyl where the rings are    optionally substituted by 1 to 2 radicals selected from the group of    hydrogen, fluorine, chlorine, bromine, nitro and-   R³ is hydrogen, and the salts, solvates and solvates of the salts    thereof.

The invention further relates to a process for preparing the compoundsof the formula (I), characterized in that compounds of the generalformula (II)

in which

-   R¹ and A have the abovementioned meaning, and-   X is hydroxyl or a suitable leaving group,    are reacted with a compound of the general formula (III)    R²R³NH  (III),    in which-   R² and R³ have the abovementioned meaning,-   where appropriate in an inert solvent, where appropriate in the    presence of a condensing agent and where appropriate in the presence    of a base,    and the resulting compounds (I) where appropriate are converted with    the appropriate (i) solvents and/or (ii) bases or acids into the    solvates, salts or solvates of the salts thereof.

If X is a leaving group, chlorine, mesyloxy, isobutyloxycarbonyloxy,pentafluorophenoxy or polymer-bound4-carboxy-2,3,5,6-tetrafluorophenoxy, in particular chlorine, arepreferred.

Examples of inert solvents are halohydrocarbons such as methylenechloride, trichloromethane, tetrachloromethane, trichloroethane,tetrachloroethane, 1,2-dichloroethane or trichloroethylene, ethers suchas diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran,glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbonssuch as benzene, xylene, toluene, hexane, cyclohexane or petroleumfractions, or other solvents such as nitromethane, ethyl acetate,acetone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide,acetonitrile or pyridine, with preference for dimethylformamide,methylene chloride, tetrahydrofuran or chloroform.

Condensing agents are, for example, carbodiimides such as, for example,N,N′-diethyl-, N,N′-dipropyl-, N,N′-diisopropyl-,N,N′-dicyclohexylcarbodiimide,N-(3-di-methylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC),N-cyclohexyl-carbodiimide-N′-propyloxymethylpolystyrene(PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfateor 2-tert-butyl-5-methylisoxazolium perchlorate, or acylamino compoundssuch as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, orpropanephosphonic anhydride, or isobutyl chloroformate, orbis(2-oxo-3-oxazolidinyl)phosphoryl chloride orbenzotriazolyloxy-tri(dimethyl-amino)phosphonium hexafluorophosphate, orO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TPTU) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) orbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), or mixtures thereof.

It may be advantageous where appropriate to use these condensing agentsin the presence of an auxiliary nucleophile such as, for example,1-hydroxybenzotriazole (HOBt).

HATU, or the combination ofN-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC)and 1-hydroxybenzotriazole (HOBt) in dimethylformamide is particularlypreferred.

Examples of bases are alkali metal carbonates such as, for example,sodium or potassium carbonate or bicarbonate, or organic bases such astrialkylamines, e.g. triethylamine, or N-methylmorpholine,N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

The process of the invention is preferably carried out in a temperaturerange from room temperature to +50° C. under atmospheric pressure.

The compounds of the general formulae (II) and (III) are known or can besynthesized by known processes from the appropriate precursors (cf., forexample, Kato et al. Chem. Pharm. Bull. 1995, 43, 1351-1357).

Thus, for example, 1-azabicyclo[2.2.2]oct-3-ylacetic acid can beobtained from quinuclidin-3-one by a Wittig-Horner reaction followed byhydrogenation and ester hydrolysis as shown in the synthesis schemebelow.

The compounds of the invention of the general formula (I) are suitablefor use as medicaments for the treatment and/or prophylaxis of diseasesin humans and/or animals.

The compounds of the invention show a valuable range of pharmacologicaleffects which could not have been predicted.

They are notable as ligands, especially agonists, on the α7 nAChR.

The compounds of the invention can, because of their pharmacologicalproperties, be employed alone or in combination with other medicamentsfor the treatment and/or prevention of cognitive impairments, especiallyof Alzheimer's disease. Because of their selective effect as α7 nAChRagonists, the compounds of the invention are particularly suitable forimproving perception, concentration, learning or memory, especiallyafter cognitive impairments like those occurring for example insituations/diseases/syndromes such as mild cognitive impairment,age-associated learning and memory impairments, age-associated memoryloss, vascular dementia, craniocerebral trauma, stroke, dementiaoccurring after strokes (post-stroke dementia), post-traumaticcraniocerebral trauma, general concentration impairments, concentrationimpairments in children with learning and memory problems, attentiondeficit hyperactivity disorder, Alzheimer's disease, vascular dementia,Lewy body dementia, dementia with degeneration of the frontal lobes,including Pick's syndrome, Parkinson's disease, progressive nuclearpalsy, dementia with corticobasal degeneration, amyotrophic lateralsclerosis (ALS), Huntington's disease, multiple sclerosis, thalamicdegeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia,schizophrenia with dementia or Korsakoff's psychosis.

The compounds of the invention can be employed alone or in combinationwith other medicaments for the prophylaxis and treatment of acute and/orchronic pain (for a classification, see “Classification of Chronic Pain,Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms”,2nd edition, Meskey and Begduk, editors; IASP Press, Seattle, 1994),especially for the treatment of cancer-induced pain and chronicneuropathic pain like, for example, that associated with diabeticneuropathy, postherpetic neuralgia, peripheral nerve damage, centralpain (for example as a consequence of cerebral ischemia) and trigeminalneuralgia, and other chronic pain such as, for example, lumbago,backache (low back pain) or rheumatic pain. In addition, these activeingredients are also suitable for the therapy of primary acute pain ofany origin and of secondary states of pain resulting therefrom, and forthe therapy of states of pain which were formerly acute and have becomechronic.

The compounds of the invention can be employed alone or in combinationwith other active ingredients for the treatment of acute or chronicneurodegenerative disorders such as, for example, stroke, craniocerebraltrauma, spinal cord injuries, Parkinson's disease, Huntington's disease,Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis(ALS) and Niemann Pick disease.

The in vitro effect of the compounds of the invention can be shown inthe following assays:

1. Determination of the Affinity of Test Substances for α7 nAChR byInhibition of [³H]-methyllycaconitine Binding to Rat Brain Membranes

The [³H]-methyllycaconitine binding assay is a modification of themethod described by Davies et al. (Neuropharmacol. 1999, 38, 679-690).

Rat brain tissue (hippocampus or whole brain) is homogenized inhomogenization buffer (10% w/v). [0.32 M sucrose, 1 mM EDTA; 0.1 mMphenylmethylsulfonyl fluoride (PMSF), 0.01% (w/v) NaN₃, pH 7.4, 4° C.]at 600 rpm in a glass homogenizer. The homogenate is centrifuged(1000×g, 4° C., 10 min) and the supernatant is removed. The pellet isresuspended (20% w/v) and the suspension is centrifuged (1000×g, 4° C.,10 mM). The two supernatants are combined and centrifuged (15 000×g, 4°C., 30 min). The pellet obtained in this way is referred to as the P2fraction.

The P2 pellet is washed twice with binding buffer (50 mM Tris-HCl, 1 mMMgCl₂, 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, pH 7.4), and centrifuged (15000×g, 4° C., 30 min).

The P2 membranes are resuspended in binding buffer and incubated in avolume of 250 μl (amount of membrane protein 0.1-0.5 mg) in the presenceof 1-5 nM [³H]-methyllycaconitine, 0.1% (w/v) BSA (bovine serum albumin)and various concentrations of the test substance at 21° C. for 2.5 h.The non-specific binding is determined by incubation in the presence of1 μM α-bungarotoxin or 100 μM nicotine or 10 μM MLA(methyllycaconitine).

The incubation is stopped by adding 4 ml of PBS (20 mM Na₂HPO₄, 5 mMKH₂PO₄, 150 mM NaCl, pH 7.4, 4° C.) and filtering through type A/E glassfiber filters (Gelman Sciences) which have previously been placed in0.3% (v/v) polyethyleneimine (PEI) for 3 h. The filters are washed twicewith 4 ml of PBS (4° C.), and the bound radioactivity is determined byscintillation measurement. All the assays are carried out in triplicate.The dissociation constant K_(i) of the test substance was determinedfrom the IC₅₀ of the compounds (concentration of the test substance atwhich 50% of the ligand bound to the receptor is displaced), thedissociation constant K_(D) and the concentration L of[³H]-methyllycaconitine using the equation K_(i)=IC₅₀/(1+L/K_(D)).

In place of [³H]-methyllycaconitine it is also possible to employ otherα7 nAChR-selective radioligands such as, for example,[¹²⁵I]-α-bungarotoxin or nonselective nAChR radioligands together withinhibitors of other nAChRs.

The data on the in vitro effects of the compounds of the invention areshown in Table A:

TABLE A Example No. K_(i) [nM] 1 120 2 200 3 280 4 42 5 170

The suitability of the compounds of the invention for the treatment ofcognitive impairments can be shown in the following animal models:

2. Object Recognition Test

The object recognition test is a memory test. It measures the ability ofrats (and mice) to distinguish between familiar and unfamiliar objects.

The test is carried out as described by Blokland et al., NeuroReport1998, 9, 4205-4208; A. Ennaceur, J. Delacour, Behav. Brain Res. 1988,31, 47-59; A. Ennaceur, K. Meliani., Psychopharmacology 1992, 109,321-330; and Prickaerts et al., Eur. J. Pharmacol. 1997, 337, 125-136.

In a first run, a rat is confronted in an otherwise empty observationarena of relatively large size by two identical objects. The rat willinvestigate, i.e. sniff round and touch, both objects extensively. In asecond run, after an interval of 24 hours, the rat is put in theobservation arena again. One of the familiar objects has now beenreplaced by a new, unfamiliar object. If a rat recognizes the familiarobject; it will concentrate on investigating the unfamiliar object.However, after 24 hours, a rat has normally forgotten which object itinvestigated in the first run, and it will therefore inspect bothobjects to the same extent. Administration of a substance with alearning- and memory-improving effect will lead to a rat recognizing theobject seen in the first run 24 hours previously as familiar. It willinvestigate the new, unfamiliar object in more detail than the familiarone. This memory ability is expressed in a discrimination index. Adiscrimination index of zero means that the rat investigates bothobjects, the old and the new, for equal times; that is to say it has notrecognized the old object and reacts to both objects as if they wereunfamiliar and new. A discrimination index greater than zero means thatthe rat inspects the new object longer than the old one; that is to saythe rat has recognized the old object.

3. Social Recognition Test:

The social recognition test is a test to examine the learning- ormemory-improving effect of test substances.

Adult rats housed in groups are placed singly in test cages 30 minutesbefore the start of the test. Four minutes before the start of the test,the test animal is put in an observation box. After this adaptationtime, a juvenile animal is put in with the test animal and the totaltime for which the adult animal investigates the juvenile animal ismeasured for 2 minutes (trial 1). All behaviors clearly directed at theyoung animal are measured, i.e. anogenital inspection, pursuit andgrooming, during which the old animal is no further than 1 cm, from theyoung animal. The juvenile animal is then taken out, and the adult isleft in its test cage (for 24-hour retention, the animal is returned toits home cage). The test animal is treated with substance before orafter the first test. Depending on the timing of the treatment, thelearning or the storage of the information about the young animal can beinfluenced by the substance. After a fixed period (retention), the testis repeated (trial 2). A larger difference between the investigationtimes measured in trials 1 and 2 means that the adult animal hasremembered the young animal better.

The compounds of the invention of the general formula (I) are suitablefor use as medicaments for humans and animals.

The present invention also includes pharmaceutical preparations which,besides inert, nontoxic, pharmaceutically suitable excipients andcarriers, contain one or more compounds of the general formula (I), orwhich consist of one or more compounds of the formula (I), and toprocesses for producing these preparations.

The compounds of the formula (I) are to be present in these preparationsin a concentration of from 0.1 to 99.5% by weight, preferably from 0.5to 95% by weight, of the complete mixture.

Besides the compounds of the formula (I), the pharmaceuticalpreparations may also contain other active pharmaceutical ingredients.

The abovementioned pharmaceutical preparations can be produced by knownmethods in a conventional way, for example using the excipient(s) orcarrier(s).

The novel active ingredients can be converted in a known manner intoconventional formulations such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, nontoxic, pharmaceutically suitable carriers or solvents. Inthese cases, the therapeutically active, compound should in each case bepresent in a concentration of about 0.5 to 90% by weight of the completemixture, i.e. in amounts which are sufficient to reach the stated doserange.

The formulations are produced for example by extending the activeingredients with solvents and/or carriers, where appropriate with use ofemulsifiers and/or dispersants, it being possible for example when wateris used as diluent where appropriate to use organic solvents asauxiliary solvents.

Administration takes place in a conventional way, preferably orally,transdermally or parenterally, especially perlingually or intravenously.However, it can also take place by inhalation through the mouth or nose,for example with the aid of a spray, or topically via the skin.

It has generally proved advantageous to administer amounts of about0.001 to 10 mg/kg, on oral administration preferably about 0.005 to 3mg/kg, of body weight to achieve effective results.

It may, nevertheless, be necessary where appropriate to deviate from thestated amounts, in particular as a function, of the body weight or ofthe mode of administration, of the individual behavior towards themedicament, the nature of its formulation and the time or interval overwhich administration takes place. Thus, it may be sufficient in somecases to make do with less than the aforementioned minimum amount,whereas in other cases the stated upper limit must be exceeded. Wherelarger amounts are administered; it may be advisable to divide theseinto a plurality of single doses over the day.

ABBREVIATIONS

-   DCI direct chemical ionization (in MS)-   DCM dichloromethane-   DMAP 4-N,N-dimethylaminopyridine-   DMF N,N-dimethylformamide-   DMSO dimethyl sulfoxide-   EDC N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide×HCl-   ESI electrospray ionization (in MS)-   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOBt 1-hydroxy-1H-benzotriazole×H₂O-   HPLC high pressure, high performance liquid chromatography-   LC-MS coupled liquid chromatography-mass spectroscopy-   MS mass spectroscopy-   NMR nuclear magnetic resonance spectroscopy-   PS polystyrene (resin)-   RT room temperature-   R_(t) retention time (in HPLC)-   THF tetrahydrofuran

HPLC Methods:

Method 1:

Instrument: HP 1100 with DAD detection; column: Kromasil RP-18, 60 mm×2mm, 3.5 μm; eluent A: 5 ml HClO₄/l H₂O, eluent B; acetonitrile;gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B; flowrate: 0.75 ml/min; temperature: 30° C.; detection: UV 210 nm.

Method 2:

Column: Kromasil 100 C-18, 125 mm×3 mm, 5 μm; eluent A: 0.2% HClO₄,eluent B: acetonitrile; gradient: 0 min 5% B, 5 min 95% B; flow rate:1.25 ml/min; temperature: 40° C.; detection: UV 210 nm.

STARTING COMPOUNDS Example 1A Quinuclidin-3-one

100 g (0.62 mol) of quinuclidin-3-one hydrochloride are suspended in 2 lof methanol. At 0° C., a solution of 33.4 g (0.62 mol) of sodiummethoxide in 250 ml of methanol is slowly added dropwise. The mixture isstirred at room temperature for 16 h. The resulting precipitate isfiltered off with suction, and the filtrate is concentrated in vacuo.The residue is partitioned between chloroform and water and extractedwith chloroform. The combined organic phases are dried over sodiumsulfate and concentrated in vacuo. 58.8 g (75.9% of theory) of the titlecompound are obtained.

MS (DCI): m/z=126 (M+H)⁺, 143 (M+NH₄)⁺

¹H-NMR (300 MHz, CDCl₃): δ=3.30 (m, 2H), 3.19-2.86 (m, 4H), 2.46 (m,1H), 1.99 (m, 41H).

Example 2A Methyl (2Z)-1-azabicyclo[2.2.2]oct-3-ylideneethanoatehydrochloride

25.3 g (0.63 mol) of sodium hydride (as 60% suspension in, mineral oil)are suspended in 480 ml of dimethylformamide. Dropwise addition of asolution of 104.8 g (0.58 mol) of trimethyl phosphonoacetate in 480 mlof dimethylformamide is followed by stirring at room temperature untilhydrogen evolution ceases. A solution of 36 g (0.29 mol) ofquinuclidin-3-one in 480 ml of dimethylformamide is added dropwise overa period of 40 minutes and then stirred at room temperature for 16 h.The reaction mixture is concentrated in vacuo, and the residue ispartitioned between water and ethyl acetate and extracted with ethylacetate. The combined organic phases are dried over sodium sulfate andconcentrated in vacuo. The residue is purified by column chromatographyon silica gel (mobile phase:dichloromethane/methanol ammonia=95:5:0.5).The material which has again been concentrated is dissolved in a littledichloromethane and mixed with ethereal HCl. The resulting precipitateis filtered off with suction and washed with diethyl ether. Drying at35° C. results in 19.53 g (31.2% of theory) of the title compound in theform of white crystals.

HPLC (Kromasil RP-18, 60×2.1 mm; eluent A: H₂O+5 ml HClO₄/l, eluent B:acetonitrile; gradient: 0-4.5 min 98% A→90% B, 4.5-6.5 min 90% B; flowrate: 0.75 ml/min; temp.: 30° C.; UV detection at 210 nm): R_(t)=2.40min.

MS (DCI): m/z=182 (M+H)⁺, 199 (M+NH₄)⁺, 363 (2M+H)³⁰

¹H-NMR (500 MHz, DMSO-d₆): δ=11.56 (broad s, 1H), 5.97 (m, 1H) 4.32 (m,2H), 3.66 (s, 3H), 3.27 (m, 4H), 2.84 (m, 1H), 2.13-1.92 (m, 2H),1.91-1.69 (m, 2H);

¹³C-NMR (125 MHz, DMSO-d₆): δ=165.72, 155.95, 113.08, 53.55, 51.28,45.29, 30.14, 22.41.

Example 3A 1-Azabicyclo[2.2.2]oct-3-ylacetic acid hydrochloride

13.5 g (62 mmol) of methyl(2Z)-1-azabicyclo[2.2.2]oct-3-ylideneethanoate are dissolved in 200 mlof methanol and, under argon, 1 g of palladium on activated carbon (10%)is added. The reaction mixture is stirred under a hydrogen atmosphere(atmospheric pressure) at room temperature for 16 h. It is filteredthrough kieselguhr and washed with methanol. The filtrate is mixed with50 ml of 1 N hydrochloric acid, concentrated in vacuo and dried underhigh vacuum. The residue is heated in 100 ml of 32% strengthhydrochloric acid under reflux for 5 h. The mixture is concentrated invacuo, codistilled twice with toluene and dried under high vacuum. 11.8g of the product are obtained in a purity of 89% (77% of theory).

HPLC (Kromasil RP-18, 60×2.1 mm; eluent A: H₂O+5 ml HClO₄/l, eluent B:acetonitrile; gradient: 0-4.5 min 98% A→90% B, 4.5-6.5 min 90B; flowrate 0.75 ml/min; temp.: 30° C.; UV detection at 210 nm): R_(t)=0.80min.

MS (DCI): m/z=170 (M+H)⁺, 339 (2M+H)⁺

¹H-NMR (200 MHz, DMSO-d₆): δ=12.32 (broad s, 1H), 10.61 (s, 1H), 3.38(m, 1H), 3.14 (m, 4H), 2.76 (dd, 1H), 2.67-2.22 (m, 4H), 2.01-1.55 (m,4H).

Example 4A 6-Methyl bromo-1-benzothiophene-2-carboxylate

3.76 g (35.5 mmol) of methyl mercaptoacetate are slowly added dropwiseto a suspension of 1.93 g (48.3 mmol) of sodium hydride (as 60%suspension in mineral oil) in 65 ml of DMSO at room temperature. Afterhydrogen evolution ceases, a solution of 6.54 g (32.2 mmol) of4-bromo-2-fluorobenzaldehyde in 10 ml of DMSO is added. After 10 min,the reaction mixture is stirred into 200 ml of ice-water, and theresulting precipitate is isolated. The Solid is washed twice with waterand dried in vacuo at 50° C. 4.06 g (46.4% of theory) of the titlecompound are obtained.

¹H-NMR (200 MHz, DMSO-d₆): δ=8.42 (d, 1H), 8.22 (s, 1H), 7.98 (d, 1H),7.65 (dd, 1H), 3.90 (s, 3H).

HPLC (method 1): R_(t)=5.3 min.

MS (ESIpos): m/z=270 (M⁺).

Example 5A 6-Bromo-1-benzothiophene-2-carboxylic acid

A solution of 4.0 g (14.8 mmol) of methyl6-bromo-1-benzothiophene-2-carboxylate in 40 ml of a 1:1 mixture of THFand 2 N potassium hydroxide solution is stirred at room temperature for2 h. The solvent is removed in vacuo, and the residue is acidified withconcentrated hydrochloric acid. The resulting precipitate is filteredoff with suction, washed with water and dried in vacuo at 50° C. 3.55 g(93.5% of theory) of the desired product are obtained.

¹H-NMR (400 MHz, DMSO-d₆): δ=13.48 (broad s, 1H), 8.38 (s, 1H), 8.22 (s,1H), 7.96 (d, 1H), 7.63 (m, 1H).

HPLC (method 1): R_(t)=4.5 min.

Example 6A 6-Bromo-1-benzothiophene-2-amine hydrochloride

0.92 ml (4.28 mmol) of diphenyl phosphorazidate are added to a solutionof 1 g (3.89 mmol) of 6-bromo-1-benzothiophene-2-carboxylic acid and1.35 ml (7.78 mmol) of N,N-diisopropylethylamine in 10 ml of DMF at 0°C. After 2 h at 0° C., the reaction mixture is added to ice-water andneutralized with acetic acid. The resulting precipitate is filtered offwith suction and washed with water. The still moist solid is suspendedin 5 ml of xylene, added dropwise to 1 ml of boiling tert-butanol andheated under reflux for 3 h. After cooling, the solvent is removed invacuo. The residue is dissolved in 4 M HCl in dioxane and stirred atroom temperature for 1 h. The resulting precipitate is filtered off withsuction and dried in vacuo. 294 mg (28.1% of theory) of the titlecompound are obtained.

HPLC (method 1): R_(t)=5.5 min.

MS (ESIpos): m/z=228 (M+H)⁺ (free base).

Example 7A Pentafluorophenyl (1-azabicyclo[2.2.2]oct-3-yl)acetatehydrochloride

358 mg (1.94 mmol) of pentafluorophenol, 120.5 mg (0.63 mmol) of EDC and1 drop of N,N-diisopropylethylamine are added to a solution of 100 mg(0.49 mmol) of 1-azabicyclo[2.2.2]oct-3-ylacetic acid hydrochloride in 4ml of dichloromethane at 0° C. The mixture is stirred at roomtemperature for 18 h. The contents of the flask are concentrated invacuo and dried under high vacuum. The resulting crude product isemployed without further purification in the following stages.

Example 8A 4-Hydroxy-2,3,5,6-tetrafluorobenzoic acid Bound to aPolymeric Support Resin

51.2 g of polystyrene-aminomethyl resin (loading 1.36 mmol/g, 69.6 mmol;from Argonaut Technologies, USA) are suspended in 700 ml of DMF. 41.6 g(107.8 mmol) of HOBt and 24.1 g (114.8 mmol) of4-hydroxy-2,3,5,6-tetrafluorobenzoic acid are added. After 15 min, 16.9ml (107.8 mmol) of N,N′-diisopropylcarbodiimide are added to thereaction mixture while stirring gently, and it is then stirredovernight. It is filtered, and the remaining resin is washed with DMF.The resulting resin is resuspended in 450 ml of DMF, mixed with 8.26 ml(83.5 mmol) piperidine and shaken. After 2 h, filtration is repeated andthe remaining resin is added to a solution of 120 ml of 1 M hydrochloricacid in 500 ml of DMF and shaken for a further 2 h. Renewed filtrationis followed by washing with 500 ml each of DMF, THF and DCM. Drying invacuo at 50° C. results in 77.2 g of the polymer-bound title compound.

Example 9A4-{(2-(1-Azabicyclo[2.2.2]oct-3-yl)acetoxy}-2,3,5,6-tetrafluorobenzoicacid Bound to a Polymeric Support Resin

2 g of the polymeric support resin from Example 8A (loading about 1.36mmol/g, 2.72 mmol) are suspended in 20 ml of DMF and shaken with 1.23 g(5.98 mmol) of 1-azabicyclo[2.2.2]oct-3-ylacetic acid hydrochloride and130 mg (1.09 mmol) of DMAP for 10 min. Then 1.06 ml (6.80 mmol) ofN,N′-diisopropylcarbodiimide are added, and the mixture is shakenovernight. The resin is filtered off with suction, washed twice eachwith 20 ml each of DMF, THF and DCM and dried under high vacuum. 2.318 gof the polymer-bound title compound are obtained.

EXEMPLARY EMBODIMENTS Example 12-(1-Azabicyclo[2.2.2]oct-3-yl)-N-(7-bromo-1-benzothien-2-yl)acetamidehydrochloride

162.3 mg (0.79 mmol) of the racemic 1-azabicylo[2.2.2]oct-3-ylaceticacid are introduced together with 120 mg (0.53 mmol) of3-bromo-1-berizothiophene-2-amine and 300.0 mg (0.79 mmol) of HATU at 0°C. into DMF. Addition of 102.0 mg (0.79 mmol) ofN,N-diisopropylethylamine is followed by stirring for 30 min. A further204.0 mg (1.58 mmol) of N,N-diisopropylethylamine are added, and themixture is stirred at RT overnight. Purification takes place bypreparative HPLC. The product is dissolved in a little acetonitrile andmixed with an excess of 1 N ethereal HCl. The solvent is stripped off invacuo. 12 mg (5% of theory) of the title compound are obtained.

HPLC (Kromasil RP-18, 60×2.1 mm; eluent A: H₂O+5 ml HClO₄/l, eluent B:acetonitrile; gradient: 0-4.5 min 98% A→90% B, 4.5-6.5 min 90% B; flowrate: 0.75 ml/min; temp.: 30° C.; UV detection at 210 nm): R_(t)=4.20min.

MS (ESIpos): m/z=379 (M+H)⁺ (free base).

Example 22-(1-Azabicyclo[2.2.2]oct-3-yl)-N-(6-bromo-1-benzothien-2-yl)acetamidehydrochloride

89.2 mg (0.24 mmol) of pentafluorophenyl(1-azabicyclo[2.2.2]oct-3-yl)acetate hydrochloride are dissolved in 1 mlof DMF, mixed with 71.2 mg (0.31 mmol) of6-bromo-1-benzothiophene-2-amine and stirred at room temperatureovernight. 1 g of MP-carbonate (polymer-bound carbonate, capacity:2.5-3.5 mmol/g; from Argonaut Technologies, USA) is added. After 3 h,the polystyrene resin is filtered off and washed with THF. The combinedfiltrates are concentrated in vacuo, and the crude product is purifiedby preparative HPLC. The hydrochloride is prepared by mixing the productwith a mixture of 1 M hydrochloric acid and acetonitrile and againconcentrating. Drying under high vacuum results in 14 mg (14% of theory)of the title compound.

HPLC (method 1): R_(t)=4.2 min.

MS (ESIpos): m/z=379 (M+H)⁺ free base).

Example 3 2-(1-Azabicyclo[2.2.2]oct-3-yl)-N-(7-quinolinyl)acetamidehydrochloride

90.3 mg (0.24 mmol) of pentafluorophenyl(1-azabicyclo[2.2.2]oct-3-yl)acetate hydrochloride are dissolved in 1 mlof DMF, mixed with 51.6 mg (0.36 mmol) of 6-aminoquinoline and stirredat room temperature overnight. 1 g of MP-carbonate (polymer-boundcarbonate, capacity: 2.5-3.5 mmol/g; from Argonaut Technologies, USA) isadded. After 1 h, the polystyrene resin is filtered off and washed withTHF. The combined filtrates are concentrated in vacuo, and the crudeproduct is purified by preparative HPLC. The hydrochloride is preparedby mixing the product with a mixture of 1 M hydrochloric acid andacetonitrile and concentrating again. Drying under high vacuum resultsin 44 mg (50.2% of theory) of the title compound.

HPLC (method 2): R_(t)=2.8 min.

MS (DCI): m/z=296 (M+H)⁺ free base).

Example 4 2-(1-Azabicyclo[2.2.2]oct-3-yl)-N-(2-naphthyl)acetamidehydrochloride

500 mg of the polymeric support resin from Example 9A (loading about1.36 mmol/g, 0.68 mmol) are suspended in 5 ml of DMF, mixed with 77.9 mg(0.54 mmol) of 2-aminonaphthylamine and shaken at room temperature for 2days. The resin is filtered off with suction and washed twice each withTHF and DMF. The combined filtrates are concentrated in vacuo. Theresidue is taken up in methanol, mixed with some palladium on activatedcarbon (10%) and hydrogenated under atmospheric pressure overnight. Thecatalyst is filtered off over kieselguhr and washed with methanol. Theresidue obtained after concentration of the combined methanol filtrateis purified by preparative HPLC. The combined product fractions aremixed with 1 M hydrochloric acid and concentrated. Drying under highvacuum results in 13 mg (4.75% of theory) of the title compound.

HPLC (method 1): R_(t)=3.9 min.

MS (ESIpos): m/z=295 (M+H)⁺ (free base).

Example 52-(1-Azabicyclo[2.2.2]oct-3-yl)-N-(8-nitro-2-naphthyl)acetamidehydrochloride

200 mg (0.97 mmol) of 1-azabicyclo[2.2.2]oct-3-ylacetic acidhydrochloride are heated under reflux in 2 ml (27.42 mol) of thionylchloride for 2 h. The mixture is then freed of excess thionyl chloridein vacuo, and the residue is taken up in 4 ml of DMF. 0.54 ml (3.89mmol) of triethylamine, 59.4 mg (0.4 mmol) of DMAP and 183.0 mg (0.97mmol) of 8-nitro-2-naphthylamine are added to this solution. Afterreaction overnight and purification by preparative HPLC, the resultingproduct fractions are mixed with 1 M hydrochloric acid and concentratedin vacuo. Recrystallization, of the residue from isopropanol and dryingunder high vacuum result in 59 mg (15% of theory) of the title compound.

HPLC (method 1): R_(t)=3.9 min.

MS (ESIpos); m/z=340 (M+H)⁺ (free base).

The invention claimed is:
 1. A method of treating a cognitive impairmentin a patient in need thereof, comprising administering to the patient acompound represented by formula (I)

in which R¹ is 1-azabicyclo[2.2.2]oct-3-yl optionally substituted by(C₁-C₆)-alkyl, A is methylene or ethylene, R² is benzothiophenyloptionally substituted by radicals selected from the group of halogen,formyl, —CO—NR⁴R⁵, —CO—OR⁶, —NR⁷R⁸, —NR⁹—CO—R¹⁰, cyano, trifluoromethyl,trifluoromethoxy, nitro, optionally hydroxyl-, amino-, —NH—CO—R¹¹— orcyano-substituted (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkylthio, inwhich R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are independently of oneanother hydrogen, (C₁-C₆)-alkyl, phenyl or benzyl, and R³ is hydrogen or(C₁-C₆)-alkyl, or a salt thereof.
 2. The method of claim 1, wherein thecognitive impairment is Alzheimer's disease.
 3. The method of claim 2,wherein R¹ is 1-azabicyclo[2.2.2]oct-3-yl, and R² and R³ have themeaning indicated in claim 1, or a salt thereof.
 4. The method of claim3, wherein A represents a methylene; R² represents benzotriazolyloptionally substituted by 1 to 3 radicals selected from the group ofhydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro,(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, (C₁-C₄)-alkylthio, and R³ representshydrogen.
 5. The method of claim 3, where R¹ is1-azabicyclo[2.2.2]oct-3-yl, A is methylene, R² is benzothiophenyl wherethe rings are optionally substituted by 1 to 3 radicals selected fromthe group of hydrogen, halogen, cyano, trifluoromethyl,trifluoromethoxy, nitro, (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy,(C₁-C₄)-alkylthio, and R³ is hydrogen, or a salt thereof.
 6. The methodof claim 3, where R¹ is 1-azabicyclo[2.2.2)oct-3-yl, A is methylene, R²is benzothiophenyl, where the rings are optionally substituted by 1 to 2radicals selected from the group of hydrogen, fluorine, chlorine,bromine, nitro and R³ is hydrogen, or a salt thereof.
 7. A method oftreating a cognitive impairment in a patient in need thereof, comprisingadministering to the patient a pharmaceutical composition comprising: i)a compound represented by formula (I)

in which R¹ is 1-azabicyclo[2.2.2]oct-3-yl optionally substituted by(C₁-C₆)-alkyl, A is methylene or ethylene, R² is benzothiophenyloptionally substituted by radicals selected from the group of halogen,formyl, —CO—NR⁴R⁵, —CO—OR⁶, —NR⁷R⁸, —NR⁹—CO—R¹⁰, cyano, trifluoromethyl,trifluoromethoxy, nitro, optionally hydroxyl-, amino-, —NH—CO—R¹¹— orcyano-substituted (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkylthio, inwhich R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are independently of oneanother hydrogen, (C₁-C₆)-alkyl, phenyl or benzyl, and R³ is hydrogen or(C₁-C₆)-alkyl, or a salt thereof; and ii) one or more pharmaceuticallyacceptable carriers or excipients.
 8. The method of claim 7, wherein thecognitive impairment is Alzheimer's disease.
 9. The method of claim 8,wherein R¹ is 1-azabicyclo[2.2.2]oct-3-yl, and R² and R³ have themeaning indicated in claim 7, or a salt thereof.
 10. The method of claim9, wherein A represents a methylene; R² represents benzotriazolyloptionally substituted by 1 to 3 radicals selected from the group ofhydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro,(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, (C₁-C₄)-alkylthio, and R³ representshydrogen.
 11. The method of claim 9, where R¹ is1-azabicyclo[2.2.2]oct-3-yl, A is methylene, R² is benzothiophenyl,where the rings are optionally substituted by 1 to 3 radicals selectedfrom the group of hydrogen, halogen, cyano, trifluoromethyl,trifluoromethoxy, nitro, (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy,(C₁-C₄)-alkylthio, and R³ is hydrogen, or a salt thereof.
 12. The methodof claim 9, where R¹ is 1-azabicyclo[2.2.2)oct-3-yl, A is methylene, R²is benzothiophenyl, where the rings are optionally substituted by 1 to 2radicals selected from the group of hydrogen, fluorine, chlorine,bromine, nitro and R³ is hydrogen, or a salt thereof.